Article Type: Original Article ORIGINAL ARTICLE Author
26
This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record . Please cite this article as doi: 10.1111/anae.14115 This article is protected by copyright. All rights reserved Article Type: Original Article ORIGINAL ARTICLE Postoperative outcomes following cardiac surgery in non-anaemic iron replete and iron deficient patients - an exploratory study L. F. Miles, 1 S. A. Kunz, 2 L. H. Na, 3 S. Braat, 3 K. Burbury 4 and D. A. Story 5 1 Consultant, Department of Anaesthesia, 2 Registrar, Department of Cardiac Surgery, Austin Health 3 Biostatistician, Melbourne School of Population and Global Health and Melbourne Clinical and Translational Science Platform (MCATS), University of Melbourne, 4 Consultant, Department of Haematology, Victorian Comprehensive Cancer Centre, 5 Professor, Melbourne Medical School and Melbourne Clinical and Translational Science Platform (MCATS), University of Melbourne, Melbourne, Australia Correspondence to: Lachlan F. Miles Consultant Anaesthetist Department of Anaesthesia Austin Health 145 Studley Road Heidelberg Vic 3084 Australia Email: [email protected]Keywords: anemia: iron-deficiency; cardiac surgical procedures; iron; outcome assessment (health care) Short title: Influence of non-anaemic iron deficiency on outcome after cardiac surgery Author Manuscript
Article Type: Original Article ORIGINAL ARTICLE Author
Postoperative outcomes following cardiac surgery in nonanaemic
ironreplete and irondeficient patients – an exploratory studyThis
is the author manuscript accepted for publication and has undergone
full peer
review but has not been through the copyediting, typesetting,
pagination and
proofreading process, which may lead to differences between this
version and the
Version of Record. Please cite this article as doi:
10.1111/anae.14115
This article is protected by copyright. All rights reserved
Article Type: Original Article
and iron deficient patients - an exploratory study
L. F. Miles,1 S. A. Kunz,2 L. H. Na,3 S. Braat,3 K. Burbury4 and D.
A. Story
5
1 Consultant, Department of Anaesthesia, 2 Registrar, Department of
Cardiac Surgery, Austin Health 3 Biostatistician, Melbourne School
of Population and Global Health and Melbourne
Clinical and Translational Science Platform (MCATS), University of
Melbourne, 4 Consultant, Department of Haematology, Victorian
Comprehensive Cancer Centre, 5
Professor, Melbourne Medical School and Melbourne Clinical and
Translational
Science Platform (MCATS), University of Melbourne, Melbourne,
Australia
Correspondence to:
assessment (health care)
Short title: Influence of non-anaemic iron deficiency on outcome
after cardiac
surgery
Accepted: 1 October 2017
Iron-deficiency anaemia is strongly associated with poor outcomes
after cardiac
surgery. However, pre-operative non-anaemic iron deficiency (a
probable anaemia
precursor) has not been comprehensively examined in patients
undergoing cardiac
surgery, despite biological plausibility and evidence from other
patient populations of
negative effect on outcome. This exploratory, retrospective cohort
study aimed to
compare an iron deficient group of patients undergoing cardiac
surgery with an iron
replete group. Consecutive, non-anaemic patients undergoing
elective coronary artery
bypass grafting or single valve replacement in our institution
between January 2013
and December 2015 were considered for inclusion. Data from a total
of 277 patients
were analysed, and were categorised by iron status and blood
haemoglobin
concentration into iron deficient (n = 109) and iron replete (n =
168) groups.
Compared with the iron replete group, patients in the iron
deficient group were more
likely to be female (43% vs. 12%, iron deficient vs iron replete,
respectively), older,
with a mean (SD) of 64.4 (9.7) vs. 63.2 (10.3) years, and have a
higher pre-operative
EuroSCORE (median IQR[range]) of 3 (2 – 5[0-10]) vs. 3 (2 –
4[0-9]), with lower
pre-operative haemoglobin of 141.6 (11.6) vs. 148.3 (11.7) g.l-1).
Univariate analysis
suggested that iron deficient patients had a longer hospital length
of stay (7 (6 – 9 [2 –
40]) vs. 7 (5 – 8 [4 – 23]) days; p = 0.013) and fewer days alive
and out of hospital at
post-operative day 90 (83 [80 – 84]{0 – 87} vs. 83 [81 – 85]{34 –
86}, p = 0.009).
There was no evidence of an association between iron deficiency and
either lower
nadir haemoglobin, or higher requirements for blood products during
inpatient stay.
After adjusting the model for pre-operative age, sex, renal
function, EuroSCORE and
haemoglobin, the mean increase in hospital length of stay in the
iron deficient relative
to the iron replete group was 0.86 days (bootstrapped 95%
confidence interval -0.37 –
2.22, p = 0.098). This exploratory study suggests there is weak
evidence of an
association between non-anaemic iron deficiency and outcome after
cardiac surgery
after controlling for potentially confounding variables.
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Introduction
It has long been recognised that iron-deficiency anaemia is
associated with poor
outcomes after cardiac surgery. Patients proceeding to surgery with
this condition
have a higher requirement for allogeneic red blood cell
transfusion, a longer hospital
stay, incidence of acute kidney injury and 30-day mortality [1].
Patients with non-
anaemic iron deficiency who are in the early stages of iron
depletion have not been as
comprehensively studied.
While clinicians most commonly associate iron with haemoglobin
(and
oxygen carrying capacity), iron plays important roles in the
metabolism of many cell
types [2]. In other patient populations, non-anaemic iron
deficiency has been linked
to a variety of negative health outcomes, including poorer metrics
of physical and
mental wellbeing [3], and exercise capacity [4]. Consensus
statements [5] and
evidence-based guidelines [6] have extrapolated from other patient
groups (notably
pre-menopausal women, endurance athletes and heart failure) and
recommend
correction of non-anaemic iron deficiency prior to major surgery.
One of few studies
of iron deficiency, rather than anaemia alone in cardiac patients,
found that in a
sample of 100 patients, 37 had iron deficiency, with 25 being iron
deficient but not
anaemic [7]. These authors acknowledged the limitation of a small
sample in looking
for associations, with the only significant finding being increased
transfusion in the
iron deficient group.
To further determine if non-anaemic iron deficiency may have a
measurable
effect on postoperative outcome in cardiac surgery, we undertook a
retrospective
exploratory analysis of all non-anaemic elective patients who
underwent isolated
coronary artery bypass grafting or single valve replacement between
January 2013
and December 2015 who had an accurate iron status recorded
pre-operatively. We
proposed that patients who were iron deficient would have a longer
length of hospital
stay, a lower number of days alive and out of hospital (the total
number of days the
patient spent at home and alive in the first 90 days after the
initial surgical procedure),
and a higher rate of allogeneic blood transfusion and lower nadir
haemoglobin
relative to those patients who were iron replete.
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Methods
We conducted a retrospective analysis of all consecutive patients
who underwent
elective, primary, on-pump coronary artery bypass grafting (CABG)
or single valve
replacement between January 2013 and December 2015. Data that we
extracted
included a combination of prospectively collected data for
statewide audit and
outcome reporting (Australian and New Zealand Society of Cardiac
Surgery National
Audit Database), and retrospective extraction from electronic
medical records (Cerner
Corporation, North Kansas City, MO). We excluded patients from the
analysis sample
if they were anaemic at the time of pre-anaesthetic assessment,
received parenteral
iron administration in the four weeks prior to surgery, were taking
oral iron
supplementation at the time of surgery, and if iron status could
not be determined.
Anaemia was defined as a haemoglobin (Hb) of less than 120 g.l-1
for females and
less than 130 g.l-1
for men (WHO criteria) [8]. This study was formally
registered
with, and approved by the Austin Health human research ethics
committee with a
waiver of individual participant informed consent.
For the purpose of the analyses, we stratified patients into two
groups based
on iron status; iron deplete (ID) and iron replete (IR). Iron
deficiency was defined as a
serum ferritin of less than 100 μg.l-1, or 100 to 300 μg.l-1 with
transferrin saturation
(TSAT) less than 20% and/or C-reactive protein (CRP) >
5mg.ml-1
[6,9].
specifically: age (years); sex; height (cm); weight (kg);
pre-operative EuroSCORE;
previous percutaneous coronary intervention; hypercholesterolaemia;
end-stage renal
failure requiring dialysis; hypercholesterolaemia; peripheral
vascular disease; and left
ventricular ejection fraction. These variables were taken from the
previously
referenced National Audit Database, and are, in part, used for
pre-operative risk
stratification. We derived body mass index (BMI [kg.m-2]) and body
surface area
(BSA [m2]) from these data. Pre-operative laboratory assessments
included baseline
Hb (g.l-1), serum ferritin (μg.l-1), TSAT (%), CRP (mg.l-1), serum
creatinine (μmol.l-1)
and estimated glomerular filtration rate (eGFR) (ml.min-1).
Intra-operative data
included the operating surgeon, whether or not the patient received
an intra-operative
anti-fibrinolytic agent (tranexamic acid or aminocaproic acid),
time spent on
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cardiopulmonary bypass, and procedure. Postoperative data included:
total length of
acute and subacute hospital stay (days); length of intensive care
stay (days);
requirement for and details of return to theatre and the reason;
requirement for and
details of readmission to acute care within the first 90
postoperative days; nadir Hb
during hospital stay; Hb on hospital discharge; requirement for
allogeneic red blood
cell transfusion and/or blood products during inpatient stay;
inpatient mortality;
inpatient complications; and days alive and out of hospital at
post-operative day 90
(DAOH-90). Unlike more days of hospital stay, which is a negative
outcome, more
DAOH-90 is a positive outcome. With respect to inpatient
complications, stroke was
defined as an embolic cerebrovascular accident with permanent
neurological deficit,
and gastrointestinal complication was defined as acute bowel
ischaemia or upper or
lower gastrointestinal haemorrhage.
The primary outcome measure was length of inpatient stay, including
acute
inpatient care and subsequent, continuous sub-acute care or
rehabilitation. Secondary
outcomes were DAOH-90, nadir Hb, and requirement for blood products
during
inpatient stay.
We did not undertake a formal sample size calculation. Every
patient who
underwent surgery in our institution between January 2013 (when
iron studies were
included as part of routine pre-operative testing regardless of
haemoglobin) and
December 2015 was considered for inclusion. The analysis sample of
277 patients
represents a cohort 3.5-fold the size of the nearest comparable
study [7]. This sample
size allows the detection of a standardised mean difference of 0.4
standard deviation
(SD) with 90% power, and a two-sided 5% level of significance using
a two-sample t-
test and a ratio of 40:60 of ID to IR.
Continuous data are presented as mean with SD or median
(IQR[range]), if
data were considered skewed. Categorical data are presented as
frequency and
percentages. Missing data was removed variable by variable, except
where missing
data precluded the accurate assessment of iron status, in which
case the entire patient
was removed from the analysis. There were 13 missing data points in
the final
analysis cohort, all of which were CRP.
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We undertook univariate analysis to examine the differences in
baseline
demographic characteristics, clinical parameters, and
post-operative outcomes
between the ID and IR groups. For binary and categorical variables
we used the chi-
square test or Fisher’s exact test (expected count less than five).
For continuous
variables, we tested for normality using the Shapiro-Wilk test, and
analysed normally
distributed data using a two-sample t-test, and we used the
Wilcoxon rank sum test in
other situations. In addition, we analysed cumulative incidence
curves using the
Kaplan-Meier method for length of stay and DAOH-90, and compared
these between
the ID and IR groups using a log rank test.
We undertook multivariate analysis on the primary outcome, length
of
inpatient stay after surgery. A causal diagram was used to select
confounders to
include in the model: we included pre-operative age; sex; eGFR;
EuroSCORE and Hb
in the multivariate model. A 95% confidence interval of the mean
difference between
ID and IR was calculated using a bootstrap percentile interval
approach with 500
resampled datasets. We performed statistical analyses using the ‘R’
software (The R
Foundation for Statistical Computing, Vienna, Austria) and SAS,
version 9.4 (SAS
Institute, Cary, NC). We have reported this study using the STROBE
guidelines [10].
Results
We screened a cohort of 448 consecutive patients who had undergone
elective CABG
or single valve surgery during the study period (Figure 1). With
respect to subjects
excluded from data analysis, we excluded twenty-seven patients (6%)
from the
dataset as they had received a parenteral iron infusion to correct
iron deficiency prior
to surgery; 10 (2%) due to oral iron therapy; 76 (16%) due to
insufficient information
in the medical record to determine iron status; and finally 58
(13%) due to anaemia.
Of the final analysis cohort (n = 277), 109 (39%) were classified
as ID, and 168
(61%) classified IR. There were two deaths in the study
cohort.
Pre-operative characteristics and laboratory parameters for each
group are
outlined in Tables 1 and 2, respectively. Patients in the ID group
were more likely to
be female (p < 0.001), older (p = 0.007), shorter in height (p
< 0.001), and by
extension, have a higher BMI (p = 0.02). ID patients also
demonstrated a higher
EuroSCORE (p = 0.007). Height, BMI and EuroSCORE are partly
dependent on sex
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and age, and may be accounted for by the higher proportion of
female patients in the
ID group. No other significant differences with respect to
pre-operative morbidity
were noted between the groups (specifically prior percutaneous
coronary intervention,
peripheral vascular disease, hypercholesterolaemia and left
ventricular ejection
fraction < 50%). Relative to the IR group, the ID patients had a
lower pre-operative
Hb (p < 0.001), a lower serum ferritin (p < 0.001), lower
TSAT (p < 0.001) and a
lower creatinine (p = 0.002), although this did not translate to a
higher eGFR (p =
0.59).
Surgical variables are listed in Table 3. A reduction in chest
drain output at
four hours (median 210ml in ID vs 283ml in IR, p = 0.005) was
noted. Despite this
difference, it is unlikely that this metric was clinically
significant with respect to the
primary outcome measure. No other differences between the two
groups were
apparent.
We undertook both univariate and multivariate analyses. The
hospital length
of stay in the ID group was longer compared to IR group; 7 (6 – 9
[2 – 40]) vs. 7 (5 –
8 [4 – 23]) days; p = 0.013). Similarly, iron deficiency was
associated with fewer
days alive and out of hospital at day 90; 83 (80 – 84 [0 – 87]) vs.
83 (81 – 85 [34 –
86]) days, p = 0.009). The cumulative probability of hospital
length of stay (Figure 2)
and days alive and out of hospital at day 90 (Figure 3) illustrate
differences over time
between the two groups. There was no evidence of a difference in
the following:
return to theatre for any reason (p = 0.12); return to theatre for
bleeding (p > 0.99);
length of intensive care stay (p = 0.22); readmission to hospital
(p = 0.42); or
mortality (p = 0.15). Whilst the nadir Hb was lower in the ID group
(p = 0.013)
(Table 4), there was no evidence of significant differences in
allogeneic red cell
transfusion; 62 (37%) vs. 48 (44%), a difference of +7%, (95% CI -5
– 19%,) p =
0.26; or requirement for blood products (p = 0.89).
We undertook multivariate analysis of the hospital length of stay,
adjusting for
the following confounding demographic factors: pre-operative age;
sex; estimated
glomerular filtration rate; EuroSCORE; and haemoglobin. Following
multivariate
analysis, the difference in length of stay was no longer apparent,
mean 0.86 days with
bootstrapped 95% CI (-0.37 - 2.22 days), p = 0.098.
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Discussion
We conducted a single centre retrospective study of non-anaemic
patients undergoing
cardiac surgery, and found that those who were iron deficient were
likely to have a
longer postoperative in-hospital stay than patients who were iron
replete, and to have
a shorter ‘days alive and out of hospital at post-operative day
90’. However, a number
of factors are potential confounders: female sex; age;
co-morbidities (as measured by
predictive risk scoring such as EuroSCORE); and lower pre-operative
Hb.
Nevertheless, even after adjusting for these factors, the trend for
patients with iron
deficiency being in hospital up to two days longer than those who
are iron replete
persisted, despite a loss of statistical significance. The other
endpoints were not
explored in a multivariate analysis.
There is substantial biological plausibility as to why non-anaemic
iron
deficiency may independently influence postoperative outcome,
including length of
stay. Iron has an integral role in homeostasis; 65% of total body
iron is in
erythropoiesis, 10% is stored in myoglobin and about 25% is
involved in
mitochondrial function through the respiratory chain [11]. Whilst
evidence that non-
anaemic iron deficiency has a negative impact on day to day
function is limited to
smaller studies [4,12], there are data suggesting that correction
of non-anaemic iron
deficiency in fit, healthy women leads to substantial improvements
in mental
wellbeing and exercise capacity, separate to the anticipated
benefits for erythropoesis
[3,13–16]. Evidence of the impact of non-anaemic iron deficiency
has extended
beyond exercise physiology, particularly to patients with heart
failure. Multiple large,
well conducted RCTs have shown benefits of the treatment of iron
deficiency in the
presence and absence of anaemia, with reductions in all-cause
mortality and
hospitalisation due to heart failure, as well as marked
improvements in exercise
tolerance and quality of life [17–19]. These studies were
subsequently confirmed by
meta-analysis [20,21].
several possible explanations. First, non-anaemic iron deficiency
may lead to lower
starting and nadir haemoglobin, with subsequent detriment to oxygen
carrying
capacity. Second, patients with non-anaemic iron deficiency are
generally more
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unwell with more comorbidities (as suggested by the increased
EuroSCORE), with
non-anaemic iron deficiency as a non-modifiable marker of illness
that, whilst
signaling the potential for a worse outcome, cannot necessarily be
corrected. Third,
non-anaemic iron deficiency acts by an as yet undefined mechanism,
possibly related
to mitochondrial or respiratory chain function. This mechanism has
been implicated
in the role of iron deficiency in heart failure [2].
Despite the presence of good quality evidence of benefit for the
correction of
non-anaemic iron deficiency in other populations, there are limited
peri-operative
data. Piednoir and colleagues found that a non-anaemic iron
deficiency sub-group
had greater transfusion rates (p < 0.05) after a broad range of
cardiac surgical
procedures [7]. Our results showed a point estimate increase of 7%
for allogeneic
transfusion in the ID group relative to the IR group, with a
confidence interval
ranging from a small, clinically unimportant decrease to a large
clinically important
increase. This may be explained by our patient population, which
focused on surgical
procedures that carried a lower rate of blood loss (CABG and single
valve surgery).
Our study supports a key finding of Piednoir et al, that even older
women are far more
likely to be iron deficient than men [7]. The link between
menstrual blood loss and
iron deficiency in pre-menopausal women is well known [22,23]. Our
findings
suggest that this finding remains true into the post-menopausal
years, which has been
noted in previous population surveys [24]. The higher proportion of
women in the ID
group also explains the differences in body habitus between the
groups and to some
extent the EuroSCORE.
Creating a definitive link between non-anaemic iron deficiency and
poor peri-
operative outcomes is important, as opinion leaders are
increasingly advocating for
correction of non-anaemic iron deficiency in patients undergoing
major surgery. For
the most part, this advice has a strong basis in biological
plausibility, but evidence
remains limited. In a recent international consensus statement, the
authors advocate
iron supplementation in any patient with a TSAT of less than 20%,
regardless of iron
status [5], and the National Blood Authority Guidelines from
Australia suggest the
same for patients with a serum ferritin less than 100 μg.l-1
[6]. However the benefits
and risks (particularly infection) of iron therapy, including
intravenous iron in peri-
operative patients with non-anaemic iron deficiency, are unclear
[25].
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Apart from the overall impact of non-anaemic iron deficiency on
outcomes,
the incidence of anaemia and iron deficiency in this cohort, and
the marked
differences relative to other previously published studies are
worthy of further
comment. In a large, UK-wide audit of over 19,000 patients across
12 cardiac surgical
centres in 2016, Klein et al demonstrated an overall incidence of
anaemia of 31%,
with the range across individual centres being 23 – 45% [26]. In
2017, Muñoz et al
described an incidence of anaemia of 40% in a sub-group of 691
cardiac surgical
patients [27]. For those having isolated CABG the incidence was
33%, and for
isolated valve repair/replacement the incidence was 41%. In those
patients who were
not anaemic (Hb > 130 g.l-1), 45% were described as having an
abnormal iron status,
defined as absolute iron deficiency (serum ferritin < 30
μg.l-1), inadequate iron stores
(serum ferritin < 100 μg.l-1 with TSAT > 20%), or iron
sequestration (serum ferritin >
100 μg.L-1
and TSAT < 20%). In contrast, after exclusion of patients who
had
received iron supplementation or whose iron status could not be
determined, the
incidence of anaemia in our subjects was 18%, and the incidence of
non-anaemic iron
deficiency was 33%. Whilst disparities in the definitions used for
iron deficiency and
anaemia may partially explain the marked difference between our
results and those of
Klein et al and Muñoz et al, it is also likely that geographic and
population
differences (perhaps with respect to genetic makeup, diet and other
demographic
features) have a key role to play.
This study has limitations, largely as a consequence of its
retrospective and
exploratory nature. Firstly, whilst the sample size was defined by
the available data
set during the collection period, a power calculation was not
performed, and Type 2
error cannot be excluded. Nonetheless, this study was three-fold
the size of the nearest
comparable study [7]. Secondly, while data were able to be
collected for all
readmission episodes at our institution, we cannot exclude the
possibility that some
patients were readmitted to other hospitals without our knowledge,
with implications
for any associated results (including days alive and out of
hospital). Thirdly,
retrospective data collection from clinical records increases the
number of patients
with incomplete data sets. In this study, 13 individual data points
were missing, all of
which were pre-operative CRP (representing 3.8% of data points for
this variable).
However, none of these missing data prevented iron status from
being determined.
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In summary, we have undertaken a retrospective, single-centre,
cohort study of non-
anaemic patients, comparing the postoperative outcomes of an iron
deficient group
following elective CABG or single valve cardiac surgery, with an
iron replete group.
While univariate analysis suggested that patients with iron
deficiency had a longer
hospital length of stay, subsequent multivariate correction for a
variety of interacting
factors showed that this association was weak. These findings
support future,
prospective observational studies to further determine the impact
of non-anaemic iron
deficiency on important, patient-centred, postoperative outcomes,
and to appropriately
design randomised trials of interventions such as iron therapy for
this condition.
Acknowledgements
The authors would like to extend their gratitude to Associate
Professor George
Matalanis and the other surgeons of the Austin Health Department of
Cardiac Surgery
for allowing access to their patient demographic and outcome data,
and to Ms.
Margaret Shaw (cardiac surgery database manager) for her assistance
in extracting
relevant data. No external funding or competing interests
declared.
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Table 1 Pre-operative characteristics of iron deplete (ID) and iron
replete (IR)
subjects. Value are number (proportion), mean (SD) and median (IQR
[range]).
Characteristics ID
n = 109
Age (years) 66 (9.6) 63 (10.3)
Height (cm) 165.9 (9.2) 170.8 (10.1)
Weight (kg) 82.7 (17.8) 84.3 (17.6)
BMI (kg.m-2 30.0 (5.8) ) 29.5 (14.4)
BSA (m2 1.94 (0.23) ) 1.99 (0.21)
EuroSCORE 3 (2 – 5 [0 – 10]) 3 (2 – 4 [0 – 9])
Prior PCI 18 (17%) 22 (13%)
Hypercholesterolaemia 89 (82%) 134 (80%)
Peripheral vascular
LVEF > 50% 86 (79%) 122 (72%)
LVEF 40 – 50% 14 (13%) 31 (18%)
LVEF 30 – 40% 7 (6%) 10 (6%)
LVEF < 30% 2 (2%) 6 (5%)
BMI, body mass index; BSA, body surface area; PCI, percutaneous
coronary
intervention; LVEF, left ventricular ejection fraction.
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Table 2 Pre-operative laboratory parameters of iron deplete (ID)
and iron replete (IR)
subjects. Value are mean (SD) and median (IQR [range]).
Laboratory parameters ID
Haemoglobin (g.l-1 141.6 (11.5) ) 148.3 (11.7)
Ferritin (μg.l-1 75 (50 – 98 [13 - 294]) ) 242 (169 – 340) [100
-
1262]
TSAT (%) 19 (16 – 25 [4 – 42]) 27 (23 – 33 [2 - 66])
CRP (mg.l-1 1.9 (0.9 – 3.6 [0.1 – 10.0]) ) 1.8 (0.9 – 3.3 [0.3 –
26.1])
Creatinine (μmol.l-1 80 (68 – 94) [47 – 159] ) 86 (77 – 97 [45 –
704])
eGFR (ml.min-1 86 (66 – 112 [26 - 295]) ) 87 (70 – 110 [11 -
356])
TSAT, transferrin saturation; CRP, C-Reactive Protein; eGFR,
estimated Glomerular
Filtration Rate.
Table 3 Conduct of surgery variables in iron deplete (ID) and iron
replete (IR)
subjects. Value are number (proportion) and median (IQR
[range]).
Conduct of
AV surgery 26 (24%) 33 (20%)
MV Surgery 11 (10%) 11 (6%)
CPB time (min) 102 (85 – 122 [36 – 331]) 109 (85 – 129 [41 –
237])
Anti-fibrinolytic 85 (77%) 125 (72%)
Chest drain output
210 (150 – 340 [70 – 1350]) 283 (200 – 385 [60 – 3150])
CABG, Coronary Artery Bypass Grafting; AV, aortic valve; MV, mitral
valve; TV,
tricuspid valve; PV, pulmonary valve; CPB, cardiopulmonary bypass.
Significant p-
values are reported in the results section.
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Table 4 Univariate outcome analysis in iron deplete (ID) and iron
replete (IR)
subjects. Values are number (proportion) and median (IQR
[range]).
Outcomes ID
n = 109
p-value
Hospital LoS (days) 7 (6 – 9 [2 – 40]) 7 (5 – 8 [4 – 23])
0.013**
DAOH-90 (days) 83 (80 – 84 [0 –
87] )
115])
Coagulation factors or
Discharge Hb (g.l-1 96 (88 – 105 [67 –
145])
Return to OT
2 (1.8%) 4 (2.4%) > 0.99*
ICU LoS (days) 3 (2 – 3 [0 – 9]) 3 (2 – 3 [1 – 11]) 0.22**
Post-operative MI 0 (0%) 1 (0.6%) > 0.99*
Pneumonia 1 (0.9%) 5 (3.0%) 0.41*
Tracheostomy 0 (0%) 0 (0%) > 0.99*
Stroke 1 (0.9%) 1 (0.6%) > 0.99*
CVVHF 0 (0%) 2 (1.2%) 0.52*
Deep sternal wound
GI complication 1 (0.9%) 2 (1.2%) > 0.99*
Readmission 13 (11.9%) 15 (8.9%) 0.42*
Mortality 2 (1.8%) 0 (0%) 0.15*
Hb, haemoglobin; PRBC, packed red blood cells; OT, operating
theatre; LoS, length
of stay; DAOH-90, days alive and out of hospital on post-operative
day 90; MI,
myocardial infarction; CVVHF, continuous venovenous
haemofiltration; GI,
gastrointestinal. * Fisher’s exact test, ** Wilcoxon test.
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Figure legends
Figure 1 STROBE-style study flowchart outlining recruitment to and
exclusion from
the analysis sample.
Figure 2 Cumulative incidence curves for ID (-----) and IR (–––)
groups for the
primary outcome measure, length of hospital stay (days); p-value =
0.012.
Figure 3 Cumulative incidence curves for ID (-----) and IR (–––)
groups for the
secondary outcome measure, days alive and out of hospital at
post-operative day 90;
p-value = 0.009.
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t
References
1. Hung M, Ortmann E, Besser M, et al. A prospective observational
cohort study
to identify the causes of anaemia and association with outcome in
cardiac
surgical patients. Heart 2015; 101: 107-12.
2. Melenovsky V, Petrak J, Mracek T, et al. Myocardial iron content
and
mitochondrial function in human heart failure: a direct tissue
analysis.
European Journal of Heart Failure 2017; 19: 522-30
3. Favrat B, Balck K, Breymann C, et al. Evaluation of a Single
Dose of Ferric
Carboxymaltose in Fatigued, Iron-Deficient Women – PREFER a
Randomized,
Placebo-Controlled Study. Collins JF, ed. PLoS One. 2014; 9(4):
e94217.
4. Pratt JJ, Khan KS. Non-Anaemic Iron Deficiency - a disease
looking for
recognition of diagnosis: a systematic review. European Journal
of
Haematology 2015; 96: 1-11.
5. Munoz M, Acheson AG, Auerbach M, et al. International consensus
statement
on the peri-operative management of anaemia and iron deficiency.
Anaesthesia
2016; 72: 233-47.
Guidelines: Module 2. National Blood Authority 2012:
http://www.blood.gov.au/system/files/documents/pbm-module-2.pdf
(accessed
March 10, 2017)
7. Piednoir P, Allou N, Driss F, et al. Preoperative iron
deficiency increases
transfusion requirements and fatigue in cardiac surgery patients.
European
Journal of Anaesthesiology 2011; 28: 796-801.
8. Chan M. Haemoglobin concentrations for the diagnosis of anaemia
and
assessment of severity. World Health Organization 2011:
http://www.who.int/vmnis/indicators/haemoglobin/en/
9. Fitzsimons S, Doughty RN. Iron deficiency in patients with heart
failure.
European Heart Journal - Cardiovascular Pharmacotherapy 2015; 1:
58-64.
10. von Elm E, Altman DG, Egger M, et al. The Strengthening the
Reporting of
Observational Studies in Epidemiology (STROBE) Statement:
Guidelines for
Reporting Observational Studies. PLoS Medicine 2007; 4: e296.
11. Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its
importance for
human health. Journal of Research and Medical Science. 2014;
19:164-74.
12. Lamanca JJ, Haymes EM. Effects of iron repletion on VO2 max,
endurance,
A u
th o
r M
a n
t
This article is protected by copyright. All rights reserved
and blood lactate in women. Medical Science Sports Exercise 1993;
25: 1386-
92.
13. Brownlie T, Hinton PS, Giordano C, Haas JD Effect of iron
treatment on
adaptation to physical training in marginally iron-deficient
non-anemic women.
FASEB Journal 1999; 13: A572.
14. Hinton PS, Giordano C, Brownlie T, Haas JD. Iron
supplementation improves
endurance after training in iron-depleted, nonanemic women. Journal
of
Applied Physiology 2000; 88: 1103-11.
15. Brownlie T, Utermohlen V, Hinton PS, Haas JD. Tissue iron
deficiency
without anemia impairs adaptation in endurance capacity after
aerobic training
in previously untrained women. American Journal of Clinical
Nutrition 2004;
79: 437-43.
16. Brownlie T, Utermohlen V, Hinton PS, Giordano C, Haas JD.
Marginal iron
deficiency without anemia impairs aerobic adaptation among
previously
untrained women. American Journal of Clinical Nutrition 2002; 75:
734-42.
17. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous
iron sucrose
on exercise tolerance in anemic and non-anemic patients with
symptomatic
chronic heart failure and iron deficiency: A randomised,
controlled, observer-
blinded trial (FERRIC-HF). Circulation 2006; 114: 407
18. Anker SD, Comin Colet J, Filippatos G, et al. Ferric
Carboxymaltose in
Patients with Heart Failure and Iron Deficiency. New England
Journal
Medicine 2009; 361: 2436-48.
19. Okonko DO, Witkowski T, Mandal AK, Slater RM, Roughton M,
Foldes G,
Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker
SD,
Ponikowski P. GA. Effect of intravenous iron sucrose on exercise
tolerance in
anaemic and non-anaemic iron deficient patients with chronic heart
failure: a
randomised, controlled, observer-blinded trial (FERRIC-HF). Eur
Heart
Journal 2006; 27: S167.
20. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of
intravenous iron
therapy in iron-deficient patients with systolic heart failure: a
meta-analysis of
randomized controlled trials. Eur Journal of Heart Failure 2016;
18: 786-95.
21. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in
chronic heart
failure: An international pooled analysis. American Heart Journal
2013; 165:
575-82.
t
This article is protected by copyright. All rights reserved
22. Bruinvels G, Burden R, Brown N, Richards T, Pedlar C. The
prevalence and
impact of heavy menstrual bleeding among athletes and mass start
runners of
the 2015 London Marathon. British Journal of Sports Medicine 2016;
50(9):
566-76.
23. Bruinvels G, Burden R, Brown N, Richards T, Pedlar C. The
Prevalence and
Impact of Heavy Menstrual Bleeding (Menorrhagia) in Elite and
Non-Elite
Athletes. PLoS One. 2016 11: e0149881.
24. Centres for Disease Control. Iron Deficiency - United States,
1999 - 2000.
Journal of the American Medical Association 2002; 288:
2114-16.
25. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous
iron therapy in
reducing requirement for allogeneic blood transfusion: systematic
review and
meta-analysis of randomised clinical trials. British Medical
Journal 2013; 347:
f4822.
26. Klein AA, Collier TJ, Brar MS, et al. The incidence and
importance of anaemia
in patients undergoing cardiac surgery in the UK - the first
Association of
Cardiothoracic Anaesthetists national audit. Anaesthesia 2016; 71:
627-35.
27. Muñoz M, Laso-Morales MJ, Gómez-Ramírez S, Cadellas M,
Núñez-Matas
MJ, García-Erce JA. Pre-operative haemoglobin levels and iron
status in a
large multicentre cohort of patients undergoing major elective
surgery. ePub
ahead of print Anaesthesia 2017; Apr 6:
doi:10.1111/anae.13840.
A u
th o
r M
a n
t
A u
th o
r M
a n
t
References
1. Hung M, Ortmann E, Besser M, et al. A prospective observational
cohort
study to identify the causes of anaemia and association with
outcome in cardiac
surgical patients. Heart 2015; 101: 107-12.
2. Melenovsky V, Petrak J, Mracek T, et al. Myocardial iron content
and
mitochondrial function in human heart failure: a direct tissue
analysis. European
Journal of Heart Failure 2017; 19: 522-30
3. Favrat B, Balck K, Breymann C, et al. Evaluation of a Single
Dose of Ferric
Carboxymaltose in Fatigued, Iron-Deficient Women – PREFER a
Randomized,
Placebo-Controlled Study. Collins JF, ed. PLoS One. 2014; 9(4):
e94217.
4. Pratt JJ, Khan KS. Non-Anaemic Iron Deficiency - a disease
looking for
recognition of diagnosis: a systematic review. European Journal of
Haematology
2015; 96: 1-11.
5. Munoz M, Acheson AG, Auerbach M, et al. International consensus
statement
on the peri-operative management of anaemia and iron deficiency.
Anaesthesia 2016;
72: 233-47.
Guidelines: Module 2. National Blood Authority 2012:
http://www.blood.gov.au/system/files/documents/pbm-module-2.pdf
(accessed March
10, 2017)
7. Piednoir P, Allou N, Driss F, et al. Preoperative iron
deficiency increases
transfusion requirements and fatigue in cardiac surgery patients.
European Journal of
Anaesthesiology 2011; 28: 796-801.
8. Chan M. Haemoglobin concentrations for the diagnosis of anaemia
and
assessment of severity. World Health Organization 2011:
http://www.who.int/vmnis/indicators/haemoglobin/en/
9. Fitzsimons S, Doughty RN. Iron deficiency in patients with heart
failure.
European Heart Journal - Cardiovascular Pharmacotherapy 2015; 1:
58-64.
10. von Elm E, Altman DG, Egger M, et al. The Strengthening the
Reporting of
Observational Studies in Epidemiology (STROBE) Statement:
Guidelines for
Reporting Observational Studies. PLoS Medicine 2007; 4: e296.
11. Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its
importance for
human health. Journal of Research and Medical Science. 2014;
19:164-74.
A u
th o
r M
a n
t
This article is protected by copyright. All rights reserved
12. Lamanca JJ, Haymes EM. Effects of iron repletion on VO2
13. Brownlie T, Hinton PS, Giordano C, Haas JD Effect of iron
treatment on
adaptation to physical training in marginally iron-deficient
non-anemic women.
FASEB Journal 1999; 13: A572.
max, endurance,
and blood lactate in women. Medical Science Sports Exercise 1993;
25: 1386-92.
14. Hinton PS, Giordano C, Brownlie T, Haas JD. Iron
supplementation improves
endurance after training in iron-depleted, nonanemic women. Journal
of Applied
Physiology 2000; 88: 1103-11.
15. Brownlie T, Utermohlen V, Hinton PS, Haas JD. Tissue iron
deficiency
without anemia impairs adaptation in endurance capacity after
aerobic training in
previously untrained women. American Journal of Clinical Nutrition
2004; 79: 437-
43.
16. Brownlie T, Utermohlen V, Hinton PS, Giordano C, Haas JD.
Marginal iron
deficiency without anemia impairs aerobic adaptation among
previously untrained
women. American Journal of Clinical Nutrition 2002; 75:
734-42.
17. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous
iron sucrose
on exercise tolerance in anemic and non-anemic patients with
symptomatic chronic
heart failure and iron deficiency: A randomised, controlled,
observer-blinded trial
(FERRIC-HF). Circulation 2006; 114: 407
18. Anker SD, Comin Colet J, Filippatos G, et al. Ferric
Carboxymaltose in
Patients with Heart Failure and Iron Deficiency. New England
Journal Medicine
2009; 361: 2436-48.
19. Okonko DO, Witkowski T, Mandal AK, Slater RM, Roughton M,
Foldes G,
Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker
SD,
Ponikowski P. GA. Effect of intravenous iron sucrose on exercise
tolerance in
anaemic and non-anaemic iron deficient patients with chronic heart
failure: a
randomised, controlled, observer-blinded trial (FERRIC-HF). Eur
Heart Journal
2006; 27: S167.
20. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of
intravenous iron
therapy in iron-deficient patients with systolic heart failure: a
meta-analysis of
randomized controlled trials. Eur Journal of Heart Failure 2016;
18: 786-95.
21. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in
chronic heart
failure: An international pooled analysis. American Heart Journal
2013; 165: 575-82.
A u
th o
r M
a n
t
This article is protected by copyright. All rights reserved
22. Bruinvels G, Burden R, Brown N, Richards T, Pedlar C. The
prevalence and
impact of heavy menstrual bleeding among athletes and mass start
runners of the 2015
London Marathon. British Journal of Sports Medicine 2016; 50(9):
566-76.
23. Bruinvels G, Burden R, Brown N, Richards T, Pedlar C. The
Prevalence and
Impact of Heavy Menstrual Bleeding (Menorrhagia) in Elite and
Non-Elite Athletes.
PLoS One. 2016 11: e0149881.
24. Centres for Disease Control. Iron Deficiency - United States,
1999 - 2000.
Journal of the American Medical Association 2002; 288:
2114-16.
25. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous
iron therapy in
reducing requirement for allogeneic blood transfusion: systematic
review and meta-
analysis of randomised clinical trials. British Medical Journal
2013; 347: f4822.
26. Klein AA, Collier TJ, Brar MS, et al. The incidence and
importance of
anaemia in patients undergoing cardiac surgery in the UK - the
first Association of
Cardiothoracic Anaesthetists national audit. Anaesthesia 2016; 71:
627-35.
27. Muñoz M, Laso-Morales MJ, Gómez-Ramírez S, Cadellas M,
Núñez-Matas
MJ, García-Erce JA. Pre-operative haemoglobin levels and iron
status in a large
multicentre cohort of patients undergoing major elective surgery.
ePub ahead of print
Anaesthesia 2017; Apr 6: doi:10.1111/anae.13840.
A u
th o
r M
a n
t
anae_14115_f1.jpeg
A u th
anae_14115_f2.png
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anae_14115_f3.png
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M a n u s c ri p t
Minerva Access is the Institutional Repository of The University of
Melbourne
Author/s: Miles, LF;Kunz, SA;Na, LH;Braat, S;Burbury, K;Story,
DA
Title: Postoperative outcomes following cardiac surgery in
non-anaemic iron-replete and iron- deficient patients - an
exploratory study
Date: 2018-04-01
Citation: Miles, L. F., Kunz, S. A., Na, L. H., Braat, S., Burbury,
K. & Story, D. A. (2018). Postoperative outcomes following
cardiac surgery in non-anaemic iron-replete and iron-deficient
patients - an exploratory study. ANAESTHESIA, 73 (4), pp.450-458.
https://doi.org/10.1111/ anae.14115.
Persistent Link: http://hdl.handle.net/11343/293975